Dengue is the most prevalent arthropod-borne viral disease worldwide and is characterized by a range of clinical severities from self-limiting dengue fever (DF) to the more severe and life-threatening dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). The pathogenesis of DHF and DSS is poorly understood. Individuals with prior dengue virus (DENV) infection have an increased risk of developing DHF upon subsequent infection, which is thought to be mediated by a process known as Ab-dependent enhancement (ADE). Dendritic cells (DC), macrophages (M0) and B cells - the antigen-presenting cells - are likely to be important in the immunopathogenesis of dengue, but their role in disease remains ill-defined. Langerhans cells are considered primary targets of DENV but lack expression of both known receptors for DENV, DC-SIGN and MMR, as do myeloid (mDC) and plasmacytoid DC (pDC) in blood. The extent to which antigen-presenting cells are infected and activated in vivo and have aberrant function related to disease severity is not known. We hypothesize that (a) DENV infection of DC leads to elaboration of inflammatory mediators that activate circulating antigen-presenting cells, upregulating receptor expression and promoting their infection and activation; (b) this positive feedback loop is accentuated in secondary infections due to the presence of DENV-specific Ab and the predicted susceptibility of circulating DC to ADE of infection; and (c) the overall effect of DENV infection of antigen-presenting cells is to exacerbate the inflammatory response and promote dysfunction and/or loss of these cells, culminating in severe disease. Here, we will determine the capacity for DENV to infect purified human antigen-presenting cells and the role for C-type lectin receptors and ADE in this infection, and determine the consequences of direct or Ab-mediated DENV infection on cellular activation and survival. We will then determine DENV infection, activation, function and/or loss of circulating antigen-presenting cells in adult dengue patients in Recife, Brazil, and examine the relationship between these parameters and disease severity.